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The spinal muscular atrophy (SMA) therapy nusinersen, an antisense oligonucleotide (ASO), acts by redirecting splicing of the SMN1 paralogue, SMN2, to promote exon 7 inclusion and increase functional SMN expression. Now, Marasco et al. report that nusinersen can also elicit a negative effect on functional SMN2 production, by deploying the silencing histone mark H3K9me2 on the SMN2 gene, which slows RNA polymerase II (RNAPII) transcriptional elongation to promote exon 7 skipping. In SMA-patient fibroblasts, the HDAC inhibitor valproic acid (which induces chromatin opening and promotes RNAPII elongation) cooperated with a nusinersen-like ASO to enhance SMN2 exon 7 inclusion. In a mouse model of SMA, the combination improved growth, survival and neuromuscular function.
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Nature Reviews Drug Discovery21, 558 (2022)
doi: https://doi.org/10.1038/d41573-022-00115-0
References
Marasco, L. E. et al. Counteracting chromatin effects of a splicing-correcting antisense oligonucleotide improves its therapeutic efficacy in spinal muscular atrophy. Cell185, 2057–2070 (2022)